Combining two or more small molecule active ingredients into one delivery system is becoming a generally accepted approach to providing enhanced treatment of certain diseases, or as a method for increasing compliance with or timelier uptake of a second drug which complements the first active. Currently these combinations are manufactured by a pharmaceutical company as a unitary pill or tablet with fixed concentrations of each drug and sent to a distributor. The distributor then ships supplies of each finished product to a dispensing group such as a pharmacy. Then, based on a script written by a healthcare provider or under the direction of a healthcare provider, the pharmacy dispenses these tablets, pills, ointments, and the like to the patient.
Examples of binary systems can be found amongst the prescription drug listings of currently market products and in over-the-counter products as well. Fixed dose prescription drug combinations are available for treating respiratory diseases, type 2 diabetes, AIDS, and certain psychiatric disorders. And there is a growing number of binary combinations being proposed, undergoing clinical studies, or in pre-market approval review by regulatory agencies. Examples are fixed dose combinations for treating cardiovascular diseases. Recently some have proposed a so called “poly pills” combining up to 6 actives for reducing cardiovascular diseases in at-risk people, especially amongst older populations. And vaccine manufacturers have been providing clinicians with preparations which contain up to 4 components in a single dose.
For treating asthma, one example of a fixed dose combination is Advair Disckus® sold by GlaxoSmithKline. It is a combination of an inhaled steroid, fluticasone propionate, and a long-acting beta agonist, salmeterol, both of which were previously market separately for treating asthma. It is marketed as a dry powder dispensed via an oral inhaler and is available in 3 fixed dose combinations of fluticasone propionate/salmeterol: 100 mcg/50 mcg, 250 mcg/50 mcg and 500 mcg/50 mcg.
For treating type 2 diabetes, an example is Avandament®, also sold by GSK. It combines rosiglitazone maleate, a member of the thiazolidinedione (TZD) class, and metformin hydrochloride, a member of the biguanide class, in a single tablet. Rosiglitazone directly targets insulin resistance, a major underlying cause of type 2 diabetes, whereas metformin acts primarily by decreasing the production of sugar by the liver. Avandamet is available in fixed dose combinations for oral administration as tablets containing rosiglitazone maleate and metformin hydrochloride equivalent to: 1 mg rosiglitazone with 500 mg metformin hydrochloride (1 mg/500 mg), 2 mg rosiglitazone with 500 mg metformin hydrochloride (2 mg/500 mg), 4 mg rosiglitazone with 500 mg metformin hydrochloride (4 mg/500 mg), 2 mg rosiglitazone with 1,000 mg metformin hydrochloride (2 mg/1,000 mg), and 4 mg rosiglitazone with 1,000 mg metformin hydrochloride (4 mg/1,000 mg).
In the treatment of psychiatric illnesses, Lilly sells Symbyax® which is a fixed dose combination of olanzapine and fluoxetine HCl. It is the first drug-based treatment for treating bipolar depression. It is available as tablets in fixed doses of olanzapine/fluoxetine HCL: 6 mg/25 mg, 6 mg/50 mg, 12 mg/25 mg, and 12 mg/50 mg.
Binary cardiovascular drug combinations are another fertile area for investigating the benefits of multiple actives in 1 pill. Statins in combination with a drug for treating another disease associated with a cardiovascular risk factor, or other drugs also useful for treating hyperlipidemea are receiving a good deal of attention. Merck is combining simvastatin (Zocor®) with Schering-Plough's ezetimibe (Zetia®) which blocks the absorption of cholesterol in the intestines to treat abnormal lipid levels in humans. Pfizer has plans to combine atorvastatin (Lipitor®) with a long-acting calcium channel blocker amlodipine besylate (Norvasc®) a blood-pressure drug. NSAID/statin combinations are also being proposed, as exemplified by the clinical trials in progress looking at the effectiveness of combining aspirin and pravastatin.
AIDS treatment has also seen combination products, particularly that of Combivar® which is comprised of two synthetic nucleoside analogs lamivudine and zidovudine. It is a GlaxoSmithKline product.
Vaccines for bacterial and viral infections are now available as 3 or 4 component systems. For diphtheria, tetanus and pertussis there are vaccines which contain 3 components in a single shot, the so-called DTaP vaccines. Vaccination against three common childhood diseases, measles, mumps and rubella can be done with a so-called MMR vaccine. In another instance, the vaccine Infanrix IPV (GSK Biologicals) can provide enhanced immunity against measles, mumps and rubella, and poliomyelitis.
A “Polypill” has been proposed for treating cardiovascular risk [British Medical Journal (vol 326, p 1419, 1423, and 1427)]. As proposed it would contain a cocktail of six existing drugs to try to lower the four key risk factors for heart disease: cholesterol, high blood pressure, high homocysteine blood levels and blood platelet function. In the polypill proposal, a statin would be included to reduce high levels of the “bad” LDL cholesterol, slashing the risk of heart disease. Three blood pressure lowering drugs would be included to reduce risk of stroke. Folic acid would be included to reduce high homosteine levels, which can encourage the build up of fatty plaques in arteries. And finally aspirin would be added to regulate the function of blood platelets. This polypill would be a fixed dose combination. It has received mixed reviews. “It's not totally a bad idea,” says Dr Robert Bonow of the American Heart Association. “Cardiovascular disease is the leading cause of death worldwide, and we're not going to be able to do enough angioplasties to treat entire populations.” But he worries that packaging six drugs in a single, one-size-fits-all pill carries the twin dangers of unnecessary side effects for people at low risk, and, conversely, undertreating those who need more aggressive care. Along similar lines, an article in the Wall Street Journal Europe titled: “Drug Makers Offer Patients Two Pills in One” (10 Nov. 2004) noted that doctors are inclined to avoid combination drugs because they are only available currently as a fixed-dose preparation in a limited number of doses, making it difficult to customize treatment regimens or to address problems patients may have with the fixed-dose approach. A doctor Yacht was quoted as saying: “If a patient has side effects on a combination, I don't know what's causing them”.
This invention provides a way to obviate or mitigate the risks associated with a one-size-fits-all multiple component approach by giving the healthcare provider an opportunity to choose from a set of actives, select a concentration for each active from a broad range of pre-prepared strengths, and have them combined into a single formulation, a customized formulation if you will. This allows individualizing drug treatment to meet the needs of each patient based on his or her unique metabolism, current health status and medical condition.